Use of macrophages to target therapeutic adenovirus to human prostate tumors

Muthana, M., Giannoudis, A., Scott, Simon D., Fang, H.-Y., Coffelt, S.B., Morrow, F.J., Murdoch, C., Burton, J., Cross, N., Burke, B., and others. (2011) Use of macrophages to target therapeutic adenovirus to human prostate tumors. Cancer Research, 71 (5). pp. 1805-1815. ISSN 0008-5472. (doi:10.1158/0008-5472.CAN-10-2349) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

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Official URL
http://dx.doi.org/10.1158/0008-5472.CAN-10-2349

Abstract

New therapies are required to target hypoxic areas of tumors as these sites are highly resistant to conventional cancer therapies. Monocytes continuously extravasate from the bloodstream into tumors where they differentiate into macrophages and accumulate in hypoxic areas, thereby opening up the possibility of using these cells as vehicles to deliver gene therapy to these otherwise inaccessible sites. We describe a new cell-based method that selectively targets an oncolytic adenovirus to hypoxic areas of prostate tumors. In this approach, macrophages were cotransduced with a hypoxia-regulated E1A/B construct and an E1A-dependent oncolytic adenovirus, whose proliferation is restricted to prostate tumor cells using prostate-specific promoter elements from the TARP, PSA, and PMSA genes. When such cotransduced cells reach an area of extreme hypoxia, the E1A/B proteins are expressed, thereby activating replication of the adenovirus. The virus is subsequently released by the host macrophage and infects neighboring tumor cells. Following systemic injection into mice bearing subcutaneous or orthotopic prostate tumors, cotransduced macrophages migrated into hypoxic tumor areas, upregulated E1A protein, and released multiple copies of adenovirus. The virus then infected neighboring cells but only proliferated and was cytotoxic in prostate tumor cells, resulting in the marked inhibition of tumor growth and reduction of pulmonary metastases. This novel delivery system employs 3 levels of tumor specificity: the natural "homing" of macrophages to hypoxic tumor areas, hypoxia-induced proliferation of the therapeutic adenovirus in host macrophages, and targeted replication of oncolytic virus in prostate tumor cells. ©2011 AACR.

Item Type: Article
DOI/Identification number: 10.1158/0008-5472.CAN-10-2349
Additional information: Unmapped bibliographic data: LA - English [Field not mapped to EPrints] J2 - Cancer Res. [Field not mapped to EPrints] C2 - 21233334 [Field not mapped to EPrints] AD - Infection and Immunity, University of Sheffield, Medical School, Sheffield S10 2RX, United Kingdom [Field not mapped to EPrints] AD - Department of Oral and Maxillofacial Surgery, University of Sheffield, Sheffield, United Kingdom [Field not mapped to EPrints] AD - Department of Oncology, University of Sheffield, Sheffield, United Kingdom [Field not mapped to EPrints] AD - Faculty of Health and Wellbeing, Sheffield Hallam University, Sheffield, United Kingdom [Field not mapped to EPrints] AD - Department of Haematology, University of Liverpool, Liverpool, United Kingdom [Field not mapped to EPrints] AD - Medway School of Pharmacy, University of Kent, Chatham Maritime, Kent, United Kingdom [Field not mapped to EPrints] AD - Department of Infection and Immunity and Inflammation, University of Leicester, Leicester, United Kingdom [Field not mapped to EPrints] AD - Department of Biology, University of York, York, United Kingdom [Field not mapped to EPrints] AD - Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom [Field not mapped to EPrints] AD - Mount Vernon Hospital, Northwood, Middlesex, United Kingdom [Field not mapped to EPrints] AD - Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden [Field not mapped to EPrints] DB - Scopus [Field not mapped to EPrints]
Uncontrolled keywords: E1A protein, E1B protein, oncolytic adenovirus, prostate specific antigen, animal cell, animal experiment, animal model, article, cancer inhibition, cell migration, cell proliferation, clinical article, controlled study, cytotoxicity, drug delivery system, drug specificity, drug targeting, human, human cell, hypoxemia, lung metastasis, macrophage, male, mouse, nonhuman, priority journal, prostate adenocarcinoma, prostatectomy, protein expression, tumor cell, upregulation, virus replication, Adenoviridae, Adenovirus E1A Proteins, Animals, Cell Hypoxia, Electrophoresis, Polyacrylamide Gel, Humans, Macrophages, Male, Mice, Mice, Nude, Oncolytic Virotherapy, Oncolytic Viruses, Prostatic Neoplasms, Transduction, Genetic, Xenograft Model Antitumor Assays
Subjects: R Medicine
R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculties > Sciences > Medway School of Pharmacy
Depositing User: Simon Scott
Date Deposited: 01 Dec 2017 14:56 UTC
Last Modified: 29 May 2019 13:52 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/45909 (The current URI for this page, for reference purposes)
Scott, Simon D.: https://orcid.org/0000-0002-8290-0461
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